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▎药明康德内容团队编辑近日，加拿大麦克马斯特大学的科学家们发现，一种参与调控嘧啶合成过程的催化酶有望成为髓母细胞瘤治疗的关键性靶点——在小鼠模型中，阻断该酶的活性可以阻止MYC扩增型髓母细胞瘤的生长。这些研究成果现已整理发表于知名学术期刊Cancer Cell上。髓母细胞瘤是儿童中最为常见的小儿脑癌，同时它也是一种可以得到妥善治疗的肿瘤，如果在扩散前进行医疗干预，其生存率约为80%。但是除了手术之外，大多数病例需要接受化疗和放疗，这些治疗方式可能会损害大脑发育，并为日后的并发症埋下伏笔。现在，这种顽疾的治疗迎来了转机，科学家们发现使用DHODH（二氢乳清酸脱氢酶）的抑制剂成功遏制了MYC扩增型髓母细胞瘤的生长及扩散，而该亚型是髓母细胞瘤中最具侵袭性的类型。DHODH是新生嘧啶合成途径的一个关键部分，该途径影响着DNA和RNA的生成，既往已有研究表明DHODH参与了肿瘤生长过程。以DHODH作为靶点的药物已经面世，比如赛诺菲公司的Arava和Aubagio，两者均为DHODH的抑制剂并且已被美国FDA批准用于治疗类风湿性关节炎和多发性硬化症，其他的潜在适应症（包括病毒感染和其他几种癌症）仍在研究中，而本研究的发现无疑为DHODH抑制剂在髓母细胞瘤中的应用提供了理论依据。在这篇研究中，科学家们通过筛选MYC扩增型髓母细胞瘤的基因组和代谢过程，最终将目光锁定在DHODH——他们发现肿瘤细胞中新生嘧啶合成途径发生了改变，并且敲除DHODH可以阻止髓母细胞瘤的生长。图片来源：123RF随后，科学家们开始探究口服型DHODH抑制剂能否阻止髓母细胞瘤小鼠的肿瘤生长。他们使用了一种名为BAY2402234的化合物来治疗MYC扩增型髓母细胞瘤小鼠模型，直到今年1月，这种化合物分子还在被拜耳公司用于治疗急性髓系白血病和胶质瘤。研究人员发现，该化合物能够减缓髓母细胞瘤的生长并改善小鼠的生存时间，使它们的寿命从对照组的28天增加到约38天（BAY2402234治疗组平均存活时间）。虽然本研究没有评估该化合物是否对年轻小鼠的大脑发育产生影响，但研究人员发现，这种化合物对体外培养的神经干细胞没有危害。而相反，放疗会影响儿童和成人的神经干细胞，并被认为是造成与辐射相关脑损伤的主要原因；化疗也已被证明会杀死健康脑细胞，这可能是患者所描述的“化疗脑”现象的成因。正如本文的第一作者William Gwynne博士在新闻稿中所说：“这种潜在的治疗方法将使我们能够杀死杂草，并拯救发育中的大脑之花。DHODH靶点充满了希望，但我们还需要几年时间才能达到临床试验阶段。这种潜在的新疗法与目前的疗法不同，不会对发育中的大脑产生毒性。”图片来源：123RF鉴于这些研究结果以及BAY2402234已在临床试验中被证实对人体的安全性，研究人员呼吁进一步优化DHODH抑制剂在髓母细胞瘤中的临床前研究，无论是单独使用还是与其他治疗方法联合使用。研究人员在文中写道，“如果这些抑制剂分子的表现良好，那么它们应该被转化为临床研究。”药明康德为全球生物医药行业提供一体化、端到端的新药研发和生产服务，服务范围涵盖化学药研发和生产、生物学研究、临床前测试和临床试验研发、细胞及基因疗法研发、测试和生产等领域。如您有相关业务需求，欢迎点击下方图片填写具体信息。▲如您有任何业务需求，请长按扫描上方二维码，或点击文末“阅读原文/Read more”，即可访问业务对接平台，填写业务需求信息▲欲了解更多前沿技术在生物医药产业中的应用，请长按扫描上方二维码，即可访问“药明直播间”，观看相关话题的直播讨论与精彩回放参考资料：[1] Gwynne, William D et al. “Cancer-selective metabolic vulnerabilities in MYC-amplified medulloblastoma.” Cancer cell, S1535-6108(22)00500-1. 31 Oct. 2022, doi:10.1016/j.ccell.2022.10.009[2] Kill the weeds, save the flower: New treatment possibility emerges for fatal childhood brain cancer，Retrieved Nov 21st, 2022, from https://www.fiercebiotech.com/research/kill-weeds-save-flower-new-treatment-possibility-emerges-childhood-brain-cancer-0[3] McMaster University researchers pinpoint potential treatment for lethal childhood cancer，Retrieved Nov 21st, 2022, from https://www.eurekalert.org/news-releases/970698免责声明：药明康德内容团队专注介绍全球生物医药健康研究进展。本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。版权说明：本文来自药明康德内容团队，欢迎个人转发至朋友圈，谢绝媒体或机构未经授权以任何形式转载至其他平台。转载授权请在「药明康德」微信公众号回复“转载”，获取转载须知。分享，点赞，在看，聚焦全球生物医药健康创新

New research out of McMaster University found a recently abandoned Bayer compound halted the growth of an aggressive form of pediatric medulloblastoma in mouse models. Brain tumors have overtaken leukemia as the deadliest childhood cancer. The MYC gene-amplified type of medulloblastoma is the deadliest of the four subgroups, forming highly malignant tumors characterized by therapy resistance and disease recurrence. Even in the cases that are "curable," the cure comes at a steep price for this vulnerable population. "We often use mortality as our success measure with cancer treatment," William Gwynne, a postdoc at McMaster and first author of the study, told BioSpace. "Unfortunately, that's not an accurate measuring stick to how well we're doing with cancer treatment. Because even though 70% of medulloblastoma patients will be cured with standard of care - chemotherapy and radiation - almost 100% of them will have what we call neurotoxic second delay," he continued. This refers to a series of neurocognitive and developmental deficits. Gwynne joined Dr. Sheila Singh's lab for his postdoc training, intrigued by her approach to studying cancer using a comparative developmental biology perspective. Singh is a pediatric neurosurgeon, so this is a need acutely felt in her own patient population. The Singh Lab team utilized genome-wide CRISPR screening to compare medulloblastoma to neural stem cells. They identified the genes highly essential for survival of the cancer cells, but non-essential to the stem cells. A collaboration with J. Rafael Montenegro-Burke from the University of Toronto dug into the metabolic profiles of the neural cells versus the medulloblastoma cells. Both the gene research and metabolic research pointed at the same thing, which got the research team "really, really excited." An Excellent Druggable Target "It turns out that this enzyme, DHODH, which fuels the production of these pyrimidine molecules, was an excellent druggable target," Gwynne said. "It was being pursued in other cancer types like leukemia. But nobody had pursued this in brain cancer yet." The team utilized the DHODH inhibitor created by Bayer, BAY2402234, due to its ability to highly penetrate the blood-brain barrier, something other inhibitors like brequinar were unable to do. The compound had been in a Bayer-sponsored trial for patients with acute myeloid leukemia, but in January the trial was terminated due to "lack of sufficient clinical benefit." Gwynne pointed to selection of the "right patients" as being the potential key benefit of a DHODH inhibitor. The research zeroed in on a specific set of patients with MYC-driven medulloblastoma because the DHODH pathway is particularly high in those cells. Inhibiting the DHODH in these cells evokes metabolic stress to halt the cycle progression and induce cell death. An important factor in any new research is reproducibility. Singh and Gwynne's research was published Nov. 10 in Cancer Cell. In August, two other papers were published in Cancer Cell, one targeting IDH mutant glioma and another studying a near-universally fatal brainstem tumor. These two papers came to the same conclusion as Singh's lab. All three teams utilized BAY2402234 to inhibit DHODH for three different kinds of brain cancers, and all signs point to it being a promising approach to stopping brain tumor growth. Gwynne and Singh are most excited about this potential new treatment approach because of its cancer-targeting effects with minimal impact on healthy cells. Current, standard treatments like radiation and chemotherapy don't distinguish between normal and cancer cells. Neurotoxic effects from these therapies leave 40-100% of pediatric brain tumor survivors with cancer-related cognitive impairment. "It's just amazing how this is really a cancer-selected metabolic vulnerability," Singh told BioSpace. Neuro Stem Cells Relatively Untouched "Only the cancer cells are disabled by this drug. The neuro stem cells are... relatively untouched by the drug at the same dose," she said. This is important because clinical trial subjects are small children with pools of stem cells that are rapidly divided into developing and creating new organs and laying down new pathways in the brain. "So, it's absolutely essential that any drug we use doesn't target those developing cell populations." In the lab, Gwynne observed how gaunt and sickly the mice treated with chemo and radiation were, as is typical in these studies. In stark contrast, the mice treated with the Bayer compound were "running around the cage happy and healthy." Those mice also outlived the mice receiving traditional treatments. "This single agent DHODH inhibitor was as effective as current standard of care in this mouse model without the side effects of the mice becoming really, really sick and getting really, really skinny like they normally do," Gwynne said. Due to the low-toxicity profile, Singh said a Phase I clinical trial is the next logical step. Bayer has yet to contact her, but a lot of interest has surfaced since the paper's publishing. "I've been contacted by drug developers who are interested and they're asking me questions like, do you think this could translate to clinical trials?Our papers have reenergized interest around that compound." BioSpace reached out to Bayer for comment but had not heard back at the time of this publication.